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High Risk Neuroblastoma Study 1.7 of SIOP-Europe (SIOPEN)

Information source: St. Anna Kinderkrebsforschung
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Neuroblastoma

Intervention: Vincristine (Drug); Aldesleukin (Drug); ch14.18/CHO (Drug); Carboplatin (Drug); Etoposide (Drug); Cisplatin (Drug); Cyclophosphamide (Drug); Doxorubicin (Drug); G-CSF (Drug); Busulfan (Drug); Melphalan (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: St. Anna Kinderkrebsforschung

Official(s) and/or principal investigator(s):
Ruth L Ladenstein, MD, MBA, cPM, Principal Investigator, Affiliation: St. Anna Kinderkrebsforschung

Overall contact:
Ruth L Ladenstein, MD, MBA, cPM, Phone: 0043140470, Ext: 4750, Email: ruth.ladenstein@ccri.at


This is a randomised study of the European SIOP Neuroblastoma Group (SIOPEN) in high-risk neuroblastoma (stages 2, 3, 4 and 4s MYCN-amplified neuroblastoma, stage 4 MYCN non amplified > 12 months at diagnosis).

The protocol consists of a rapid, dose intensive induction chemotherapy (R3 randomisation -

Rapid COJEC vs modified N7), peripheral blood stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy (BuMel) followed by peripheral blood stem cell

rescue, radiotherapy to the site of the primary tumour and immunotherapy (R4 randomisation -

isotretinoin and ch14. 18/CHO, with or without aldesleukin (IL-2). In the induction phase, all patients with stage 4 neuroblastoma and those with stage 4s MYCN-amplified neuroblastoma will be randomised (R3) to Rapid COJEC or modified N7; localised patients receive Rapid COJEC (Rapid COJEC is given with G-CSF support based on the results of the R0 randomisation running between 2002 and 2005). Following induction treatment peripheral blood stem cell harvest (PBSCH) will be performed and complete excision of the primary tumour will be attempted. Patients with an inadequate metastatic response to allow BuMel MAT followed by PBSCR at the end of induction should receive 2 TVD (Topotecan, Vincristine, Doxorubicin) cycles. After Rapid COJEC induction, localised patients will proceed to consolidation. Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without segmental chromosomal alterations (SCA) are thought to have a good prognosis and will stop treatment after induction therapy and surgery to the primary tumour. Consolidation consists of BuMel MAT (following the results of the R1 randomisation) followed by peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour. During the immunotherapy phase, patients will be randomised (R4) to immunotherapy with isotretinoin (13-cis-RA) and ch14. 18/CHO, with or without aldesleukin (IL-2).

Clinical Details

Official title: High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Event Free Survival (R1: MAT therapy)

Event Free Survival (R4: immunotherapy)

Complete metastatic response (R3: Induction therapy)

Event free survival (R3: Induction therapy)

Detailed description: In this protocol the term high-risk neuroblastoma refers to children with either

- disseminated disease (INSS stage 4: about 40 to 50% of all neuroblastoma) over the age

of one or

- INSS stage 2 and 3 disease with amplification of the MycN proto-oncogene

Between 10% and 20% of children with stage 3 and occasional patients with stage 2 disease are characterised by amplification of the MycN gene in their tumours. This biological characteristic has clearly been shown to be associated with a greater risk of relapse and death from disease progression. These patients may benefit from very aggressive treatment and, based on this hypothesis, they are included in this protocol.

- Infants (< 12 months at diagnosis) with MYCN amplified tumours are included. Children

with this type of presentation and age represent the largest neuroblastoma subgroup. Their prognosis remains poor in most cases and our ability to predict the clinical course and the outcome of the individual patient is modest. Primary objectives: R0 randomisation: R0 was opened with the study activation in February 2002 and closed in November 2005. The randomised use of G-CSF during COJEC induction resulted in the recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia R1 randomisation: R1 was opened with the study activation in February 2002 and closed in 10/2010 following the results showing significant superiority of myeloablative therapy (MAT) with busulfan and melphalan over continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT. R2 randomisation: R2 was activated in November 2006 (13-cis retinoic acid +/- chimeric ch14. 18/CHO antibody), modified in July 2009 and suspended in August 2013. R2 randomisation tested the hypothesis that immunotherapy with chimeric 14. 18/CHO and subcutaneous aldesleukin (IL-2, Proleukin®), following MAT and autologous stem cell transplantation, in addition to differentiation therapy with 13-cis retinoic acid, will improve 3-year EFS in patients with high-risk neuroblastoma. R3 randomisation: R3 was opened in June 2011 and tests the hypothesis that modified N7 induction regimen will improve the metastatic response rates or event free survival (EFS) as compared to Rapid COJEC. R4 randomisation: R4 was activated in April 2014. The SIOPEN long term infusion (LTI) ch14. 18/CHO trial successfully lowered the toxicity profile by prolonging the infusion time of the same total ch14. 18/CHO antibody dose of 100mg/m² to 10 days of continuous infusion in relapsed /refractory patients. Hence the HRNBL1. 7/SIOPEN study committee wishes to implement this more favourable immunotherapy dosing schedule for the time till the induction question R3 is answered and the HRNBL1. 7/SIOPEN trial may be closed. Considering the high R2 dropout rate of patients unable to receive all immunotherapy cycles in the IL-2 s. c. combination treatment arm and not observing this effect in the current SIOPEN LTI trial, it is suggested to address the IL-2sc dose in the new R4. Therefore the potential synergistic effect of sc IL-2 will be addressed again with 50% of the original s. c. IL-2 dose. The IL-2sc dose will hence be reduced to 3 x 106 IU IL-2/m2/day s. c. in the HR-NBL1/SIOPEN R4 amendment instead of 6 x 106 IU IL-2/m2/day s. c as used in the SIOPEN LTI trial. In the second week of each IT course s. c.IL-2 will be given on days 2, 4, 6, 8, 10 in parallel to the ch14. 18/CHO ctn infusion and not during the first 5 days in week 2 as scheduled in the SIOPEN LTI trial.


Minimum age: 1 Month. Maximum age: 21 Years. Gender(s): Both.


Inclusion Criteria:

- • Established diagnosis of neuroblastoma according to the International Neuroblastoma

Staging System (INSS).

- Age below 21 years.

- High risk neuroblastoma defined as either:

1. INSS stage 2, 3, 4, and 4s with MYCN amplification, or 2. INSS stage 4 without MYCN amplification aged > 12 months at diagnosis

- Patients who have received no previous chemotherapy except for one cycle of

etoposide and carboplatin (VP16/Carbo). In this situation patients will receive Rapid COJEC induction and the first Rapid COJEC cycle may be replaced by the first cycle VP16/Carbo (etoposide / carboplatin).

- Written informed consent, including agreement of parents or legal guardian for

minors, to enter a randomised study if the criteria for randomisation are met.

- Tumour cell material available for determination of biological prognostic


- Females of childbearing potential must have a negative pregnancy test. Patients

of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.

- Registration of all eligibility criteria with the data centre within 6 weeks

from diagnosis.

- Provisional follow up of 5 years.

- National and local ethical committee approval.

Exclusion Criteria: Any negative answer concerning the inclusion criteria of the study


Locations and Contacts

Ruth L Ladenstein, MD, MBA, cPM, Phone: 0043140470, Ext: 4750, Email: ruth.ladenstein@ccri.at

Sydney Children's Hospital, Sydney, Australia; Recruiting

Univ.-Klinik für Kinder- und Jugendheilkunde Graz, Graz, Austria; Recruiting

Univ.Klinik f. Kinder-u. Jugendheilkunde Innsbruck, Innsbruck, Austria; Recruiting

Landes- Kinderklinik Linz, Linz, Austria; Recruiting

St. Johanns Spital LKH Salzburg, Salzburg, Austria; Recruiting

Cliniques universitaires St-Luc, Brussels, Belgium; Recruiting

Hôpital des Enfants, Brussels, Belgium; Recruiting

University Hospital Gent, Gent, Belgium; Recruiting

UZ Gasthuisberg, Leuven, Belgium; Recruiting

CHR Citadelle, Lüttich, Belgium; Recruiting

Clinique de l'Espérance, Montegnee, Belgium; Recruiting

University Hospital Motol, Prague, Czech Republic; Recruiting

Aarhus Universitetshospital, Aarhus, Denmark; Recruiting

National State Hospital, Copenhagen, Denmark; Recruiting

University Hospital of Odense, Odense, Denmark; Recruiting

Skejby Hospital, Skejby, Denmark; Recruiting

Hopital d'Enfants Dijon, Dijon, France; Recruiting

CHU de Grenoble, Grenoble, France; Recruiting

CHR Pellegrin, Le Pellerin, France; Recruiting

Centre Oscar Lambret de Lille, Lille, France; Recruiting

Hopitaux de Marseille La Timone, Marseille, France; Recruiting

CHR de Nantes, Nantes, France; Recruiting

Hôpital Trousseau Paris, Paris, France; Recruiting

Institut Curie, Paris, France; Recruiting

Hôpital American Memorial Hospital, Reims, France; Recruiting

CHU-Saint Etienne, Saint Etienne, France; Recruiting

Hopital Hautepierre-CHU Strasbourg, Strasburg, France; Recruiting

Hôpital D'Enfants de Toulouse, Toulouse, France; Recruiting

Institut Gustave Roussy, Villejuif, France; Recruiting

"A&P Kyriakou" Children's Hospital, Athens, Greece; Recruiting

Aghia Sophia Children's Hospital, Athens, Greece; Recruiting

Madarász Children Hospital Budapest, Budapest, Hungary; Recruiting

Semmelweis University of Budapest, Budapest, Hungary; Recruiting

Dublin: OLHSC, Dublin, Ireland; Recruiting

Rambam Medical Centre, Haifa, Israel; Recruiting

Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel; Recruiting

Sheba Medical Center, Tel Aviv, Israel; Recruiting

Ospedale G. Salesi, Ancona, Italy; Recruiting

Universitŕ degli studi di Bari, Bari, Italy; Recruiting

Ospedali Riuniti, Bergamo, Italy; Recruiting

Ospedale S. Orsola, Bologna, Italy; Recruiting

Ospedale Regionale per le Microcitemie, Cagliari, Italy; Recruiting

Azienda Ospedaliera di Cosenza, Cosenza, Italy; Recruiting

Azienda Ospedaliera A. Meyer, Firenze, Italy; Recruiting

Istituto Giannina Gaslini, Genua, Italy; Recruiting

Istituto Nazionale Tumori di Milano, Milano, Italy; Recruiting

Azienda Ospedal. Univ. di Modena, Modena, Italy; Recruiting

Sec. Univ. degli Studi di Napoli - Policlinico, Napoli, Italy; Recruiting

Clinica di Oncoematologia Pediatrica Padova, Padova, Italy; Recruiting

Ospedale dei Bambini, Palermo, Palermo, Italy; Recruiting

Azienda Ospedaliera Universitaria di Parma-Oncoematologia Pediatrica, Parma, Italy; Recruiting

Policlinico San Matteo, Pavia, Italy; Recruiting

Ospedale Civile Spirito Santo, Pescara, Italy; Recruiting

Ospedale "Infermi ", Rimini, Italy; Recruiting

Policlinico Borgo Roma, Roma, Italy; Recruiting

Ospedale Bambino Gesu, Rome, Italy; Recruiting

Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Recruiting

O.I.R.M. - S. Anna, Torino, Italy; Recruiting

Istituto per l'Infanzia "Burlo Garofolo", Trieste, Italy; Recruiting

Haukeland University Hospital, Bergen, Norway; Recruiting

Rikshospitalet, Oslo, Norway; Recruiting

University Hospital of North-Norway, Tromso, Norway; Recruiting

Medical University of Bialystok, Bialystok, Poland; Recruiting

Medical University of Bydgoszcz, Bydgoszcz, Poland; Recruiting

Childrens' Hospital in Chorzów, Chorzów, Poland; Recruiting

University Children's Hospital, Cracow, Poland; Recruiting

Medical University in Gdansk, Gdansk, Poland; Recruiting

Upper Silesian Centre of Child and Mother's Care, Katowice, Poland; Recruiting

Children's University Hospital in Lublin, Lublin, Poland; Recruiting

University of Medical Sciences Poznan, Poznan, Poland; Recruiting

Institute Mother and Child, Warschau, Poland; Recruiting

Wroclaw Medical University, Wroclaw, Poland; Recruiting

Ipofg-Crl, Lissabon, Portugal; Recruiting

University Hospital F. D. Roosevelt, Banská Bystrica, Slovakia; Recruiting

H. General de Alicante, Alicante, Spain; Recruiting

H. de Donostia Ntra. Sra. de Aranzazu, Aranzazu, Spain; Recruiting

Hospital Vall d`Hebron, Barcelona, Spain; Recruiting

Hospital de Cruces, Bilbao, Spain; Recruiting

H. General de Galicia, Galicia, Spain; Recruiting

Complejo Hospitalario de Jaen, Jaen, Spain; Recruiting

H . Materno-Infantil Teresa Herrera, La Coruna, Spain; Recruiting

H. Monteprincipe, Madrid, Spain; Recruiting

Hospital 12 de Octubre, Madrid, Spain; Recruiting

H Central de Asturias, Oviedo, Spain; Recruiting

H. C. U. de Salamanca, Salamanca, Spain; Recruiting

Hospital Virgen del Rocio, Sevilla, Spain; Recruiting

Carlos Haya, Valencia, Spain; Recruiting

Hospital Infantil La Fe, Valencia, Spain; Recruiting

H Clinico-Universitario, Zaragoza, Spain; Recruiting

Queen Silvia's Children's Hospital, Göteburg, Sweden; Recruiting

Childrens Hospital Linkoping, Linkoping, Sweden; Recruiting

University Children's Hospital, Geneva, Switzerland; Recruiting

CHUV, Lausanne, Switzerland; Recruiting

Aberdeen: Royal Aberdeen Children's Hospital, Aberdeen, United Kingdom; Recruiting

Royal Belfast Hospital for Sick Children, Belfast, United Kingdom; Recruiting

Birmingham Children's Hospital, Birmingham, United Kingdom; Recruiting

Bristol Royal Hospital for Children, Bristol, United Kingdom; Recruiting

Addenbrooke's NHS Trust, Cambridge, United Kingdom; Recruiting

Llandough Hospital, Cardiff, United Kingdom; Recruiting

Edinburgh Royal Hospital for Sick Children, Edinburgh, United Kingdom; Recruiting

Glasgow Royal Hospital for Sick Children, Glasgow, United Kingdom; Recruiting

Leeds: St James's University Hospital, Leeds, United Kingdom; Recruiting

Leicester Royal Infirmary, Leicester, United Kingdom; Recruiting

Liverpool: Alder Hey Children's Hospital, Liverpool, United Kingdom; Recruiting

Great Ormond Street Hospital, London, United Kingdom; Recruiting

St Bartholomew's Hospital, London, United Kingdom; Recruiting

UCLH University College London Hospital, London, United Kingdom; Recruiting

Royal Manchester Children's Hospital, Manchester, United Kingdom; Recruiting

Newcastle: Royal Victoria Infirmary, Newcastle, United Kingdom; Recruiting

Nottingham: Queen's Medical Centre, Nottingham, United Kingdom; Recruiting

Oxford: John Radcliffe Hospital, Oxford, United Kingdom; Recruiting

Sheffield Children's Hospital, Sheffield, United Kingdom; Recruiting

Southampton General Hospital, Southhampton, United Kingdom; Recruiting

Royal Marsden Hospital, Sutton, United Kingdom; Recruiting

St. Anna Kinderspital, Vienna, Austra 1090, Austria; Recruiting
Ruth Ladenstein, MD, MBA, cPM, Phone: 0043140470, Ext: 4750, Email: ruth.ladenstein@ccri.at

Additional Information

Starting date: February 2002
Last updated: October 30, 2014

Page last updated: August 23, 2015

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